Search

Abstract: Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases with chronic, progressive, and irreversible characteristics, affecting nearly 50 million older adults worldwide. The pathogenesis of AD includes the formation of senile plaques, the abnormal aggregation of tau protein and the gradual degeneration and death of cerebral cortical cells. The main symptoms are memory loss, cognitive decline and behavioral disorders. Studies indicate that cannabidiol (CBD) possesses various pharmacological activities, including anti-inflammatory, anti-oxidation and neuroprotective activities. It has been suggested as a potential multi-target medicine for the treatment of AD. In this review, we aim to summarize the underlying mechanisms and protective effects of CBD on signaling pathways and central receptors involved in the pathogenesis of AD, including the endocannabinoid system (eCBs), the Transient receptor potential vanilloid type 1(TRPV1) receptor, and the Peroxisome proliferator-activated receptor (PPAR) receptor.

We conducted a prospective randomized controlled trial to compare the radiological and clinical outcomes of Sanders type III calcaneal fractures treated with percutaneous prodding reduction and K-wire fixation via a sinus tarsi approach (PPRKF) versus open reduction and internal fixation (ORIF). Fifty-one patients with closed, unilateral, Sanders type III calcaneal fractures were randomly assigned to the PPRKF group (n = 26) or the ORIF group (n = 25). The clinical outcomes evaluated were time to surgery, blood loss, operative time, hospital stay, wound healing time, wound complications, and Maryland foot score. Radiological results were evaluated on lateral and axial X-rays and computed tomography images and included Böhler's angle, Gissane's angle, and calcaneal width. Compared with the ORIF group, the PPRKF group had shorter time to surgery, shorter operative time, less blood loss, shorter hospital stay, shorter wound healing time, and fewer wound complications (p.001). The postoperative Böhler's angle, Gissane's angle, and calcaneal width in both groups were significantly better than those measured preoperatively (p.001) and did not differ between the PPRKF group and ORIF group (p.05). Regarding clinical results, there was no significant difference in Maryland foot score between the two groups at 12 months after surgery (p.05). Both PPRKF and ORIF can result in satisfactory clinical function. PPRKF is superior to ORIF in reducing the time to surgery, operative time, blood loss, hospital stay, wound healing time, and wound complications.

To analyze the distribution and types of pathogenic bacteria of Mooren’s ulcer and the activation mechanism of T lymphocytes to provide reference for the treatment of Mooren’s ulcer, 156 patients (162 eyes) who were in the hospital were rolled into the observation group. During the same period, 134 healthy people were rolled into the control group. The distribution of infectious pathogens in the observation group was identified. Then, flow cytometry was adopted to separate and detect the peripheral blood lymphocytes of patients, and RT-PCR was used to detect levels of the transcription factor T-bet, GATA-3, and Stat5 in peripheral blood mononuclear cells (PBMCs). It was found that fungal pathogens accounted for 43.59%; the bacterial infection rate was 40.38%. In the observation group, the CD4, CD8, and C25 were expressed more (P < 0.01), and the CD45 and CD45R were expressed less than the control group (P < 0.05); the proportion of Th1 cells was obviously higher (P < 0.01); the expression of T-bet and GATA-3 was obviously higher (P < 0.05), the percentage of HLA-DR in CD4+ and HLA-DR, CD-25, and CD69 in CD8+ positive cells was obviously higher (P < 0.05). In conclusion, fungal infection rate of Mooren’s ulcer is relatively high, peripheral blood T cells and their subgroups are abnormally activated, and T cell activation is related to the pathogenesis of Mooren’s ulcer.

Objectives Postmenopausal osteoporosis (PMO) and osteoporotic fracture seriously impair human health in developed countries. The present study aims to explore whether sensory nerves, calcitonin gene-related peptide (CGRP), and brain-derived serotonin are related to bone loss in ovariectomized (OVX) rats. Methods Female rats were grouped into the ovariectomized (OVX) and sham surgery (SHAM) groups. Immunocytochemistry, western blotting, and qPCR were performed to detect CGRP expression in the femurs. The expression levels of serotonin and CGRP in the spinal cord and brainstem were estimated using western blotting, immunofluorescence, and qPCR. ELISA was used to evaluate the serum biomarkers of bone formation and resorption. Bone mineral density was measured using dual-energy X-ray (DXA) analysis. Femur microstructure was imaged by Micro CT. P values less than 0.05 were considered statistically significant. Results ELISA showed that serum bone alkaline phosphatase (BALP), tartrate-resistant acid phosphatase (TRAP), β-crosslaps, and β-ctx were increased in the OVX group. In the OVX group, in vivo bone mineral density, trabecular bone mineral density, bone volume fraction (BV/TV), and trabecular number (Tb. N) were significantly decreased, while trabecular spacing (Tb. Sp) and trabecular bone pattern factor (Tb. Pf) were markedly increased. In the OVX group, the expression levels of CGRP of the femur were significantly downregulated. In contrast, CGRP and serotonin expression was increased in the spinal cord of the OVX group. Serotonin expression was increased in the brainstem, brainstem nucleus raphe magnus (RMG), and nucleus raphe dorsalis (DRN). Conclusion Our results indicated that the activation of osteoclast triggered the release of CGRP from nociceptive sensory nerve fibers and transmitted this painful stimulus to the dorsal horn of the spinal cord to release increased CGRP. The descending serotonergic inhibitory system was activated by increased CGRP levels of the spinal cord and promoted serotonin release in the brainstem RMG, DRN, and the spinal cord, contributing to the decreased CGRP level in bone tissue, which revealed a novel mechanism of bone loss in PMO.

Objective This study aimed to examine the association between physical education classes and PA among adolescents from 50 low- and middle-income countries (LMICs). Methods A self-reported questionnaire from the Global School-based Student Survey (GSHS) was used to collect information on participation frequency of physical education classes and being physically active over the last week, as well as other control variables (e.g., sex, age, country, sedentary behavior). Multivariable logistic regression and a pooled meta-analysis were performed to explore the association and compared country-wise differences. Results Included adolescents aged from 13 to 17 years (n = 187,386, %boys = 51.7; mean age = 14.6 years), the prevalence of sufficient PA (meeting the PA guidelines) was 14.9%. The prevalence of 5 days or more to engage in physical education classes was 16.5%. Compared with adolescents who had 0 days for physical education classes, higher participation frequency was more likely related to sufficient PA (OR: 1 day = 1.34, 2 days = 1.66, 3 days = 1.67, 4 days = 1.79, 5 days or more = 2.46), these findings were also observed in both sexes. A moderate inconsistency on the association across the included countries was found (I2 = 53%, p Conclusions Participating in more physical education classes may be an effective approach to increase physical activity levels among adolescents in LMICs. However, promoting physical activity levels among adolescents in LMICs through physical education classes should consider more country-specific factors.

Four polyketide-amino acid derivatives, pardinumones A-D (1-4), were isolated from the wild mushroom Tricholoma pardinum. Their structures together with absolute configurations were characterized by means of spectroscopic data analyses, as well as calculated electronic circular dichroism (ECD) and NMR with sorted training set (STS) protocol analysis. Compounds 1-4 exhibited antibacterial activity against Staphylococcus aureus, Staphylococcus epidermidis, and Escherichia coli with MIC values in the range of 6.25-50 μg/mL.

Background Acute pancreatitis (AP) is a common digestive disease with increased incidence globally but without internationally licenced pharmacological therapy. Moderately severe and severe acute pancreatitis (MSAP/SAP) contributes predominately for its morbidities and mortality and has been managed in West China Hospital for decades using the traditional Chinese medicinal formula chaiqin chengqi decoction (CQCQD). The current study tests whether the early administration of CQCQD will result in improved clinical outcomes in predicted MSAP/SAP patients. Methods This is a single-centre, randomised, controlled, double-blind pragmatic clinical trial. AP patients aged 18–75 admitted within 72 h of onset will be assessed at admission for enrolment. We excluded the predicted mild acute pancreatitis (Harmless Acute Pancreatitis Score > 2 at admission) and severe organ failure (Sequential Organ Failure Assessment [SOFA] score of respiratory, cardiovascular, or renal systems > 3) at admission. Eligible patients will be randomly allocated on a 1:1 basis to CQCQD or placebo control administration based on conventional therapy. The administration of CQCQD and placebo is guided by the Acute Gastrointestinal Injury grade-based algorithm. The primary outcome measure will be the duration of respiratory failure (SOFA score of respiratory system ≥ 2) within 28 days after onset. Secondary outcome measures include occurrence of new-onset any organ failure (SOFA score of respiratory, cardiovascular, or renal system ≥ 2) and new-onset persistent organ failure (organ failure lasts > 48 h), dynamic surrogate biochemical markers and clinical severity scores, gut-centred treatment modalities, local complications status, intensive care need and duration, surgical interventions, mortality, and length of hospital stay. Follow-up will be scheduled on 6, 12, and 26 weeks after enrolment to assess AP recurrence, local complications, the requirement for surgical interventions, all-cause mortality, and patient-reported outcomes. Discussion The results of this study will provide high-quality evidence to appraise the efficacy of CQCQD for the early management of AP patients. Trial registration Chictr.org.cn Registry (ChiCTR2000034325). Registered on 2 July, 2020.

Non‐small cell lung cancer (NSCLC) is the most common subtype of lung cancer, and it is characterized by a high incidence. It is important to understand the molecular mechanisms that determine the progression and metastasis of NSCLC in order to develop more effective therapies and identify novel diagnostic indicators of NSCLC. RSPH14 has been reported to be related to multiple human diseases, including duodenal adenocarcinoma and meningiomas, but the role of RSPH14 in NSCLC remains unclear. The present study aimed to investigate the molecular function and clinical significance of RSPH14 in NSCLC. Analyses of public datasets and clinical samples demonstrated that RSPH14 expression was upregulated in NSCLC samples compared with normal samples. In addition, high RSPH14 expression was associated with a shorter overall survival time in patients with NSCLC. Notably, RSPH14 knockdown suppressed the proliferation and cell cycle progression and enhanced the apoptosis of NSCLC cells. Mechanically, tandem mass tag analysis demonstrated that RSPH14 can affect multiple processes, including the AMPK signaling pathway, calcium ion import regulation, glucose transmembrane transporter activity, and glucose transmembrane transport. Taken together, the results of the present study suggest that RSPH14 may be a promising prognostic factor and therapeutic target for NSCLC., RSPH14 expression was upregulated in NSCLC samples compared with normal samples and was involved in regulating multiple processes, including glucose transmembrane transport and the AMPK signaling pathway. High expression of RSPH14 enhanced proliferation and cell cycle progression and suppressed the apoptosis of NSCLC cells, thereby promoting the progression of NSCLC.

Postoperative neurocognitive disorder (PND) increases the length of hospital stay, mortality, and risk of long-term cognitive impairment. Perioperative sleep disturbance is prevalent and commonly ignored and may increase the risk of PND. However, the role of perioperative sleep disturbances in PND remains unclear. Nocturnal sleep plays an indispensable role in learning, memory, and maintenance of cerebral microenvironmental homeostasis. Hospitalized sleep disturbances also increase the incidence of postoperative delirium and cognitive dysfunction. This review summarizes the role of perioperative sleep disturbances in PND and elucidates the potential mechanisms underlying sleep-deprivation-mediated PND. Activated neuroinflammation and oxidative stress; impaired function of the blood-brain barrier and glymphatic pathway; decreased hippocampal brain-derived neurotrophic factor, adult neurogenesis, and sirtuin1 expression; and accumulated amyloid-beta proteins are associated with PND in individuals with perioperative sleep disorders. These findings suggest that the improvement of perioperative sleep might reduce the incidence of postoperative delirium and postoperative cognitive dysfunction. Future studies should further investigate the role of perioperative sleep disturbance in PND.

Purpose: The present study combined resting-state functional connectivity (FC) and Granger causality analysis (GCA) to explore frontostriatal network dysfunction in unilateral acute tinnitus (AT) patients with hearing loss. Methods: The participants included 42 AT patients and 43 healthy control (HC) subjects who underwent resting-state functional magnetic resonance imaging (fMRI) scans. Based on the seed regions in the frontostriatal network, FC and GCA were conducted between the AT patients and HC subjects. Correlation analyses were used to examine correlations among altered FC values, GCA values, and clinical features in AT patients. Results: Compared with HCs, AT patients showed a general reduction in FC between the seed regions in the frontostriatal network and nonauditory areas, including the frontal cortices, midcingulate cortex (MCC) , supramarginal gyrus (SMG), and postcentral gyrus (PoCG) . Using the GCA algorithm, we detected abnormal effective connectivity (EC) in the inferior occipital gyrus (IOG), MCC, Cerebelum_Crus1, and PoCG. Furthermore, correlations between disrupted FC/EC and clinical characteristics, especially tinnitus distress-related characteristics, were found in AT patients. Conclusions: Our work demonstrated abnormal FC and EC between the frontostriatal network and several nonauditory regions in AT patients with hearing loss, suggesting that multiple large-scale network dysfunctions and interactions are involved in the perception of tinnitus. These findings not only enhance the current understanding of the frontostriatal network in tinnitus but also serve as a reminder of the importance of focusing on tinnitus at an early stage.

Fibrosis serves a critical role in driving atrial remodelling‐mediated atrial fibrillation (AF). Abnormal levels of the transcription factor PU.1, a key regulator of fibrosis, are associated with cardiac injury and dysfunction following acute viral myocarditis. However, the role of PU.1 in atrial fibrosis and vulnerability to AF remain unclear. Here, an in vivo atrial fibrosis model was developed by the continuous infusion of C57 mice with subcutaneous Ang‐II, while the in vitro model comprised atrial fibroblasts that were isolated and cultured. The expression of PU.1 was significantly up‐regulated in the Ang‐II‐induced group compared with the sham/control group in vivo and in vitro. Moreover, protein expression along the TGF‐β1/Smads pathway and the proliferation and differentiation of atrial fibroblasts induced by Ang‐II were significantly higher in the Ang‐II‐induced group than in the sham/control group. These effects were attenuated by exposure to DB1976, a PU.1 inhibitor, both in vivo and in vitro. Importantly, in vitro treatment with small interfering RNA against Smad3 (key protein of TGF‐β1/Smads signalling pathway) diminished these Ang‐II‐mediated effects, and the si‐Smad3‐mediated effects were, in turn, antagonized by the addition of a PU.1‐overexpression adenoviral vector. Finally, PU.1 inhibition reduced the atrial fibrosis induced by Ang‐II and attenuated vulnerability to AF, at least in part through the TGF‐β1/Smads pathway. Overall, the study implicates PU.1 as a potential therapeutic target to inhibit Ang‐II‐induced atrial fibrosis and vulnerability to AF.

Intracavitary electrocardiogram (ECG) has been widely used for PICC tip positioning in patients with a normal left heart. However, there is little information about using ECG for PICC insertion in patients with mirror dextrocardia. We report a 70-year-old stomach cancer patient with mirror dextrocardia admitted to our vascular access center for four Fr silicon Groshong PICC insertion. We successfully performed an ultrasound-guided modified Seldinger technique for insertion. First, the usual standardized ECG technique was used for tip positioning, and it failed. Then, we changed the procedure slightly, using the opposite electrode connections (RA: the first intercostal space of the midline of the left clavicle; LA: the first intercostal space of the midline of the right clavicle; and LL: the inferior margin of the right costal arch) to obtain an evident P-wave change to guide catheter placement in this case. We confirm that we can use the opposite electrodes to obtain an apparent P-wave for locating the catheter tip in patients with mirror dextrocardia.

Intervertebral disc (IVD) degeneration (IDD) is a multifactorial pathological process associated with low back pain (LBP). The pathogenesis is complicated, and the main pathological changes are IVD cell apoptosis and extracellular matrix (ECM) degradation. Apoptotic cell loss leads to ECM degradation, which plays an essential role in IDD pathogenesis. Apoptosis regulation may be a potential attractive therapeutic strategy for IDD. Previous studies have shown that IVD cell apoptosis is mainly induced by the death receptor pathway, mitochondrial pathway, and endoplasmic reticulum stress (ERS) pathway. This article mainly summarizes the factors that induce IDD and apoptosis, the relationship between the three apoptotic pathways and IDD, and potential therapeutic strategies. Preliminary animal and cell experiments show that targeting apoptotic pathway genes or drug inhibition can effectively inhibit IVD cell apoptosis and slow IDD progression. Targeted apoptotic pathway inhibition may be an effective strategy to alleviate IDD at the gene level. This manuscript provides new insights and ideas for IDD therapy.

Highlights • This study provides the prevalence estimates of physical activity, sedentary behavior, and sleep duration (isolation and combination) in a nationally representative sample (n = 114,072) of Chinese children and adolescents of grades 4–12. • Only about 5% of Chinese children and adolescents show the most ideal combination of 24-h movement behaviors. • Chinese children and adolescents with younger ages, higher parental education levels, and higher family incomes exhibit favorable 24-h movement behaviors. • Chinese children and adolescents with the most ideal 24-h movement behaviors have lower risks of overweight and obesity, especially in children of grades 4–6 and girls of grades 7–9., Background Meeting 24-h movement guidelines by children and adolescents has been associated with improved indicators of health, although it has been under-studied in China. Hence, this study aimed to investigate the prevalence of meeting the 24-h movement guidelines, its correlates, and its relationships with body mass index in children and adolescents in China. Methods Cross-sectional data from the 2017 Youth Study in China of 114,072 children and adolescents (mean age = 13.75 years, 49.18% boys) were used. Meeting 24-h movement guidelines (≥60 min of daily moderate-to-vigorous physical activity, ≤2 h of daily leisure screen time, 9–11 h and 8–10 h nightly sleep duration for 6–13-year-olds and 14–17-year-olds, respectively) and height and weight of all participants were assessed. The prevalence of meeting the 24-h movement guidelines and World Health Organization weight status categories were determined. Generalized linear models were used to determine the correlates of meeting the 24-h movement guidelines and the relationships of meeting the 24-h movement guidelines with overweight (OW) and obesity (OB). Results Only 5.12% of Chinese children and adolescents met the 24-h movement guidelines, and 22.44% were classified as OW/OB. Older children and adolescents were less likely to meet the 24-h movement guidelines. Parental education level and family income were positively related to meeting the 24-h movement guidelines. Children and adolescents meeting the 24-h movement guidelines showed lower odds ratios for OW/OB. Compared with participants meeting the 24-h movement guidelines, boys in 4th–6th grades met none of the recommendations (OR = 1.22, 95%CI: 1.06–1.40), met the screen time recommendation only (OR = 1.13, 95%CI: 1.01–1.28), met the nightly sleep duration recommendation only (OR = 1.14, 95%CI: 1.03–1.28), and had significantly higher odds ratios for OW/OB. Similar trends were observed for girls in 4th–6th grades: meeting none of the guidelines (OR = 1.35, 95%CI: 1.14–1.59), meeting sleep duration guidelines only (OR = 1.23, 95%CI: 1.08–1.39), and meeting moderate-to-vigorous physical activity + nightly sleep duration guidelines (OR = 1.24, 95%CI: 1.01–1.54). For girls in 7th–9th grades, the following trend was observed: meeting none of the guidelines (OR = 1.30, 95%CI: 1.01–1.67). Conclusion Very few Chinese children and adolescents met the 24-h movement guidelines. Age (negatively correlated), parental education level, and family income (both positively correlated) were correlates of meeting the 24-h movement guidelines. Children and adolescents meeting the 24-h movement guidelines were more likely to have lower risks for OW/OB, especially in the youngest age group (Grades 4–6); and girls in the middle age group (Grades 7–9) were also more likely to have lower risks for OW/OB. Further research studies should explore additional correlates and determinants for meeting the 24-h movement guidelines. Also, future studies should use longitudinal or interventional designs to determine the relationships between meeting the 24-h movement guidelines and OW/OB and other health indicators, while taking sex and age differences into account., Graphic Abstract Image, graphical abstract

Rationale: The onset of cytokine release syndrome (CRS) and in vivo persistence of anti-CD19 chimeric antigen receptor T (CAR-T) cells after infusion correlate with clinical responsiveness. However, there are no known baseline biomarkers that can predict the prognosis of patients with B-lineage non-Hodgkin lymphoma (B-NHL). The aim of this study was to identify blood cell populations associated with beneficial outcomes in B-NHL patients administered CAR-T cell immunotherapies. Methods: We enumerated peripheral blood and CAR-T cells by retrospectively analyzing three CAR-T cell trials involving 65 B-NHL patients. We used a preclinical model to elucidate the eosinophil mechanism in CAR-T cell therapy. Results: During an observation period up to 30 mo, B-NHL patients with higher baseline eosinophil counts had higher objective response rates than those with low eosinophil counts. Higher baseline eosinophil counts were also significantly associated with durable progression-free survival (PFS). The predictive significance of baseline eosinophil counts was validated in two independent cohorts. A preclinical model showed that eosinophil depletion impairs the intratumoral infiltration of transferred CAR-T cells and reduces CAR-T cell antitumor efficacy. Conclusion: The results of this study suggest that peripheral eosinophils could serve as stratification biomarkers and a recruitment machinery to facilitate anti-CD19 CAR-T cell therapy in B-NHL patients.

Income inequality generates structural barriers that prevent people especially those from disadvantaged backgrounds from accessing key resources. However, extant research on income inequality has mostly investigated its impact on limiting access to material but not digital resources. Digital resources have become more critical in the twenty-first century. The current research aims to explore whether income inequality is associated with individuals’ internet use. Based on an investigation of a nationally representative study of children and adolescents (n = 10,386; Mage = 11.61) from 25 provinces in China, we found that children and adolescents in more unequal provinces engaged in less internet use. Moreover, this relationship was moderated by socioeconomic background. In more unequal provinces, only children and adolescents from low-income families reported lower internet use but those from high-income families did not. These findings indicate the significance of income inequality and of the moderating role of socioeconomic condition in shaping access to digital resources.

Chronic pruritus is a symptom that commonly observed in neurological diseases. It has been hypothesized that the chronic pruritus may result from sensitization of itch-signaling pathways but the mechanisms remain obscure. In this study, we established a mouse model of chronic compression of dorsal root ganglion (CCD) and injected various pruritogenic and algogenic agents intradermally to the calf skin ipsilateral to the compressed dorsal root ganglion (DRG). Compared to the naïve mice, a significant increase in itch-related behaviors was observed in the CCD mice after the injection of pruritogens including histamine and BAM8-22, but not after the injection of capsaicin, although all the above agents evoked enhanced pain-related behaviors toward the injected site. In addition, we investigated if pruritogen-evoked activities of DRG neurons are enhanced in this model. In vivo calcium imaging revealed that compressed DRG neurons exhibited significant enhanced responses to histamine and BAM8-22. Immunoflorescent staining also showed that the histamine receptor H1 and the capsaicin receptor TRPV1 were significantly upregulated in DRG neurons. Our findings indicated that in mice modeling the sensitization of primary pruriceptive neurons may underlie the enhanced itch sensation after chronic compression of DRG neurons, and may play a role in chronic pruritus in neurological diseases.

Background Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (dlPFC) may reduce substance use and other addictive behaviours. However, the cognitive mechanisms that underpin such effects remain unclear. Impaired inhibitory control linked to hypoactivation of the prefrontal cortex may allow craving-related motivations to lead to compulsive addictive behaviours. However, very few studies have examined whether increasing the activation of the dlPFC via anodal tDCS could enhance inhibitory control over addiction-related distractors. The current study aimed to enrich empirical evidence related to this issue. Methods Thirty-three males with Internet gaming disorder underwent active (1.5 mA for 20 minutes) and sham tDCS 1 week apart, in randomized order. We assessed inhibitory control over gaming-related distractors and craving pre- and post-stimulation. Results Relative to sham treatment, active tDCS reduced interference from gaming-related (versus non-gaming) distractors and attenuated background craving, but did not affect cue-induced craving. Limitations This study was limited by its relatively small sample size and the fact that it lacked assessments of tDCS effects on addictive behaviour. Future tDCS studies with multiple sessions in larger samples are warranted to examine the effects on addictive behaviours of alterations in addiction-related inhibitory control. Conclusion These findings demonstrate that stimulation of the dlPFC influences inhibitory control over addiction-related cues and addiction-related motivation. This is the first empirical study to suggest that enhanced inhibitory control may be a cognitive mechanism underlying the effects of tDCS on addictions like Internet gaming disorder. Our finding of attenuated background craving replicated previous tDCS studies. Intriguingly, our finding of distinct tDCS effects on 2 forms of craving suggests that they may have disparate underlying mechanisms or differential sensitivity to tDCS. Clinical trials # NCT03352973.

Background and Purpose: The defective colonic mucus barrier is a feature of ulcerative colitis (UC) that enables increased bacterial contact with the epithelium, which triggers mucosal damage, and gastrin has been reported to be able to promote healing through the cholecystokinin 2 receptor (CCK2R) signaling to increase epithelial regeneration and protect against colonic injury. However, the role of gastrin in UC remains unclear. Experimental Approach: Colonic samples from human sections and mouse models using β-arrestin1 wild-type (β-arr1-WT) and β-arrestin1 knockout (β-arr1-KO) littermates, intestinal epithelial cells specific NF-κBp65 deletion (NF-κBp65) and wild-type (NF-κBp65) mice were analyzed. The mucosal injury, goblet cells status, MUC2 expression and bacteria penetration/colonisation were examined, and the effect of gastrin in colitis was also investigated. Key Results: We demonstrate that mucus barrier loss and bacterial colonisation of the crypts were observed in colitis, and exogenous gastrin could restore the mucus barrier, reduce bacterial colonisation of the colonic crypts and alleviate colitis via CCK2R. Furthermore, targeting CCK2R by YF476, β-arrestin1 (β-arr1) deletion or intestinal epithelial NF-κBp65 deficiency breached gastrin-mediated mucus barrier restoration and mucosal protection in colitis. Conclusion and Implications: These data demonstrate that gastrin alleviates mucus barrier loss and bacterial colonisation of the colonic crypts via CCK2R/β-arr1/NF-κBp65 signaling in colitis, and this network may be a potential therapeutic target for UC.

To evaluate the long-term efficacy of Coflex dynamic stabilization device in the treatment of lumbar spinal stenosis.The clinical and imaging data of 73 patients undergoing Coflex dynamic stabilization surgery from July 2008 to June 2012 were retrospectively analyzed. All patients had a minimum of 8 years of follow-up. Clinical data were used to assess the clinical efficacy, and radiographic parameters were measured for evaluation of ASD.56 Patients were followed up for 107.6 ± 13.3 months. The visual analogue scale of pain (VAS), Owestry disability index (ODI) and Japanese Orthopedic Association Scores (JOA) improved significantly after surgery. At 6 months after surgery and the last follow-up, lumbar range of motion (ROM) was significantly lower than that before surgery (P 0.001). ROM was slightly increased at the last follow-up compared with that 6 months after operation (P 0.05). ROM of adjacent segments increased at 6 months and at the last follow-up compared with that before surgery (P 0.05). At 6 months after surgery, intervertebral space height (ISH) and intervertebral foramen height (IFH) of implanted segment was significantly higher than that before surgery (P 0.05). At the last follow-up, there was a decrease in ISH and IFH (P 0.05). During the follow-up period, a total of 11 patients (19.6%) experienced complications and 6 patients (10.7%) underwent secondary surgery.Coflex interspinous process dynamic stabilization is effective in the long-term treatment of lumbar spinal stenosis, the ISH and IFH of implanted segment could be increased in a short period of time.

Tumor growth and metastasis are the major causes of high mortality in breast cancer. We previously constructed pH-sensitive nanoparticles (D/D NPs) for the codelivery of docetaxel (DTX) and dihydroartemisinin (DHA) and demonstrated that D/D NPs showed anticancer activity in breast cancer cells in vitro. The present study further investigated the therapeutic effect of D/D NPs on orthotopic breast cancer in vivo and examined the antitumor mechanism of D/D NPs. D/D NPs significantly increased the apoptosis of 4T1 cells with a synergistic effect of DTX and DHA. D/D NPs increased reactive oxygen species, reduced mitochondrial membrane potential, increased the expression of p53, and induced cytochrome c release into the cytoplasm to activate caspase-3. In an orthotopic metastatic breast cancer mouse model derived from 4T1 cells, D/D NPs inhibited tumor growth and prevented lung metastasis due to the synergistic effect of DTX and DHA. No distinct changes were observed in the histology of major organs. These results indicate that pH-sensitive D/D NP-based combination therapy may be a promising strategy for the treatment of metastatic breast cancers via the ROS-mediated mitochondrial apoptosis pathway.

To evaluate whether the efficacy of Getong Tongluo Capsule (葛酮通络胶囊, GTC, consisted of total flavone of Radix Puerariae) on improving patients’ quality of life and lowering blood pressure are superior to the extract of Ginkgo biloba (EGB) for patients with convalescent-phase ischemic stroke and primary hypertension. This randomized, positive-drug- and placebo-controlled, double-blind trial was conducted from September 2015 to October 2017. Totally 477 eligible patients from 18 hospitals in China were randomly assigned in a 2:1:1 ratio to the following interventions, twice a day for 12 weeks: (1) GTC 250 mg plus EGB-matching placebo 40 mg (237 cases, GTC group), (2) EGB 40 mg plus GTC-matching placebo 250 mg (120 cases, EGB group) or (3) GTC-matching placebo 250 mg plus EGB-matching placebo 40 mg (120 cases, placebo group). Moreover, all patients were orally administered aspirin enteric-coated tablets 100 mg, once a day for 12 weeks. The primary outcome was the Barthel Index (BI). The secondary outcomes included the control rate of blood pressure and National Institutes of Health Stroke Scale (NIHSS) scores. The incidence and severity of adverse events (AEs) were calculated and assessed. The BI relative independence rates, the clinical recovery rates of NIHSS, and the total effective rates of NIHSS in the GTC and EGB groups were significantly higher than the placebo group at 12 weeks after treatment (P 0.05). The control rate of blood pressure in the GTC group was significantly higher than the EGB and placebo groups at 12, 18 and 24 weeks after treatment (P 0.05). GTC exhibited significant efficacy in improving patients’ quality of life as well as neurological function and controlling hypertension. (Registration No. ChiCTR1800016667)

Background Although successful ablation of the accessory pathway (AP) eliminates atrial fibrillation (AF) in some of patients with Wolff‐Parkinson‐White (WPW) syndrome and paroxysmal AF, in other patients it can recur. Hypothesis Whether adding pulmonary vein isolation (PVI) after successful AP ablation effectively prevents AF recurrence in patients with WPW syndrome is unknown. Methods We retrospectively studied 160 patients (102 men, 58 women; mean age, 46 ± 14 years) with WPW syndrome and paroxysmal AF who underwent AP ablation, namely 103 (64.4%) undergoing only AP ablation (AP group) and 57 (35.6%) undergoing AP ablation plus PVI (AP + PVI group). Advanced interatrial block (IAB) was defined as a P‐wave duration of >120 ms and biphasic (±) morphology in the inferior leads, using 12‐lead electrocardiography (ECG). Results During the mean follow‐up period of 30.9 ± 9.2 months (range, 3‐36 months), 22 patients (13.8%) developed AF recurrence. The recurrence rate did not differ in patients in the AP + PVI group and AP group (15.5% vs 10.5%, respectively; P = .373). Univariable and multivariable Cox regression analyses showed that PVI was not associated with the risk of AF recurrence (hazard ratio, 0.66; 95% confidence interval, 0.26‐1.68; P = .380). In WPW patients with advanced IAB, the recurrence rate was lower in patients in the AP + PVI group vs the AP group (90% vs 33.3%, respectively; P = .032). Conclusions PVI after successful AP ablation significantly reduced the AF recurrence rate in WPW patients with advanced IAB. Screening of a resting 12‐lead ECG immediately after AP ablation helps identify patients in whom PVI is beneficial.

Oxidative stress and autophagy are the key promoters of calcium oxalate (CaOx) nephrolithiasis. Taurine is an antioxidant that plays a protective role in the pathogenesis of kidney disease. Previous studies found that taurine suppressed cellular oxidative stress, and inhibited autophagy activation. However, the effect of taurine on CaOx kidney stone formation remains unknown. In the present work, we explored the regulatory effects of taurine on CaOx crystals-induced HK-2 cell injury. Results showed that pretreatment with taurine significantly enhanced the viability of HK-2 cells and ameliorated kidney tissue injury induced by CaOx crystals. Taurine also markedly reduced the levels of inflammatory cytokines, apoptosis, and CaOx crystals deposition. Furthermore, we observed that taurine supplementation alleviated CaOx crystals-induced autophagy. Mechanism studies showed that taurine reduced oxidative stress via increasing SOD activity, reducing MDA concentration, alleviating mitochondrial oxidative injury, and decreasing the production of intracellular ROS. Taurine treatment also effectively activated Akt/mTOR signaling pathway in CaOx crystals-induced HK-2 cells both in vitro and in vivo. In summary, the current study shows that taurine inhibits ROS-dependent autophagy via activating Akt/mTOR signaling pathway in CaOx crystals-induced HK-2 cell and kidney injury, suggesting that taurine may serve as an effective therapeutic agent for the treatment of CaOx nephrolithiasis.

Childhood maltreatment has been extensively linked to adult psychopathology, but the specificity and heterogeneity within this association remains inadequately understood. Research with non-Western...

Jin Tao,1 Yang Zhang,2 Ao Shen,3 Yunxu Yang,1 Lu Diao,4 Luye Wang,1 Danwei Cai,4 Ying Hu1,4 1School of Pharmaceutical Sciences, Zhejiang Pharmaceutical College, Ningbo, Zhejiang, People’s Republic of China; 2Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, People’s Republic of China; 3School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia; 4School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Ying HuZhejiang Pharmaceutical College, No. 888, East Section, Yinxian Main Road, The Zone of Higher Education, Ningbo, Zhejiang 315100, People’s Republic of ChinaTel +86 574 8822 2707Fax +86 574 8822 3023Email pharmhawk@126.comPurpose: Osteomyelitis, particularly chronic osteomyelitis, remains a major challenge for orthopedic surgeons. The traditional treatment for osteomyelitis, which involves antibiotics and debridement, does not provide a complete solution for infection and bone repair. Antibiotics such as vancomycin (VCM) are commonly used to treat osteomyelitis in clinical settings. VCM use is limited by a lack of effective delivery methods that provide sustained, high doses to entirely fill irregular bone tissue to treat infections.Methods: We engineered a chitosan (CS)-based thermosensitive hydrogel to produce a VCM-nanoparticle (NPs)/Gel local drug delivery system. The VCM-NPs were formed with quaternary ammonium chitosan and carboxylated chitosan nanoparticles (VCM-NPs) by positive and negative charge adsorption to enhance the encapsulation efficiency and drug loading of VCM, with the aim of simultaneously preventing infection and repairing broken bones. This hydrogel was evaluated in a rabbit osteomyelitis model.Results: The VCM-NPs had high encapsulation efficiency and drug loading, with values of 60.1± 2.1% and 24.1± 0.84%, respectively. When embedded in CS-Gel, the VCM-NPs maintained their particle size and morphology, and the injectability and thermosensitivity of the hydrogel, which were evaluated by injectability test and rheological measurement, were retained. The VCM-NPs/Gel exhibited sustained release of VCM over 26 days. In vitro tests revealed that the VCM-NPs/Gel promoted osteoblast proliferation and activity against Staphylococcus aureus. In vivo, VCM-NPs/Gel (with 10 mg vancomycin per rabbit) was used to treat rabbits with osteomyelitis. The VCM-NPs/Gel showed excellent anti-infection properties and accelerating bone repair under osteomyelitis conditions.Conclusion: The reported multifunctional NPs hydrogel system for local antibiotic delivery (VCM-NPs/Gel) showed bone regeneration promotion and anti-infection properties, demonstrating significant potential as a scaffold for effective treatment of osteomyelitis.Keywords: vancomycin, chitosan, nanoparticles, injectable hydrogel, osteomyelitis

Objective Since the declaration of the coronavirus 2019 (COVID-19) outbreak as pandemic, there are reports on the increased prevalence of physical symptoms observed in the general population. We investigated the association between psychological outcomes and physical symptoms among healthcare workers. Methods Healthcare workers from 5 major hospitals, involved in the care for COVID-19 patients, in Singapore and India were invited to participate in a study by performing a self-administered questionnaire within the period of February 19 to April 17, 2020. Healthcare workers included doctors, nurses, allied healthcare workers, administrators, clerical staff and maintenance workers. This questionnaire collected information on demographics, medical history, symptom prevalence in the past month, Depression Anxiety Stress Scales (DASS-21) and the Impact of Events Scale-Revised (IES-R) instrument. The prevalence of physical symptoms displayed by healthcare workers and the associations between physical symptoms and psychological outcomes of depression, anxiety, stress, and post-traumatic stress disorder (PTSD) were evaluated. Results Out of the 906 healthcare workers who participated in the survey, 48 (5.3%) screened positive for moderate to very-severe depression, 79 (8.7%) for moderate to extremely-severe anxiety, 20 (2.2%) for moderate to extremely-severe stress, and 34 (3.8%) for moderate to severe levels of psychological distress. The commonest reported symptom was headache (32.3%), with a large number of participants (33.4%) reporting more than four symptoms. Participants who had experienced symptoms in the preceding month were more likely to be older, have pre-existing comorbidities and a positive screen for depression, anxiety, stress, and PTSD. After adjusting for age, gender and comorbidities, it was found that depression (OR 2.79, 95% CI 1.54–5.07, p = 0.001), anxiety (OR 2.18, 95% CI 1.36–3.48, p = 0.001), stress (OR 3.06, 95% CI 1.27–7.41, p = 0.13), and PTSD (OR 2.20, 95% CI 1.12–4.35, p = 0.023) remained significantly associated with the presence of physical symptoms experienced in the preceding month. Linear regression revealed that the presence of physical symptoms was associated with higher mean scores in the IES-R, DASS Anxiety, Stress and Depression subscales. Conclusions Our study demonstrates a significant association between the prevalence of physical symptoms and psychological outcomes among healthcare workers during the COVID-19 outbreak. We postulate that this association may be bi-directional, and that timely psychological interventions for healthcare workers with physical symptoms should be considered once an infection has been excluded.

To investigate progression-free survival (PFS) and event-free survival (EFS) as early efficacy endpoints in diffuse large B-cell lymphoma (DLBCL), this systematic review included phase III randomized controlled trials (RCTs), phase II trials, and retrospective studies in newly diagnosed DLBCL receiving rituximab-containing chemotherapy through databases search up to 2019. Quality control was performed, where studies with high risk of bias were excluded. Prediction models were first established using the RCTs, and then externally validated in the phase II and retrospective populations. Trial-level surrogacy analysis was conducted by correlating the logarithmic (log) hazard ratio (HR) for PFS or EFS and log HR for OS. Correlation analysis at treatment arm-level was performed between 1-, 2-, 3-, and 5-year PFS or EFS rates and 5-year OS. The correlation was evaluated using the Pearson correlation coefficient r in weighted linear regression, with weight equal to patient size. Sensitivity analyses were performed to assess the consistency of predictive model by leaving one subgroup of trials out at a time. Twenty-six phase III RCTs, 4 phase II trials and 47 retrospective studies were included. In trial-level surrogacy, PFS (r, 0.772; 95% confidence interval [CI], 0.471–0.913) or EFS (r, 0.838; 95% CI, 0.625–0.938) were associated with OS. For rituximab immunochemotherapy treatment arms in RCTs, there was a linear correlation between 1 and 5-year PFS (r, 0.813–0.873) or EFS (r, 0.853–0.931) and 5-year OS. Sensitivity analysis demonstrated reasonable overall consistency. The correlation between PFS and OS was externally validated using independent phase II, and retrospective data (r, 0.795–0.897). We recommend PFS and EFS as earlier efficacy endpoints in patients with DLBCL primarily treated with rituximab-containing immunochemotherapy.

Background The associations between various kinds of parental support and children and adolescents’ physical activity (PA) are inconclusive. This study aimed 1) to examine the associations between various kinds of parental support and children and adolescents’ moderate-to-vigorous physical activity (MVPA), and 2) to examine gender and age differences in the association between each specific kind of parental support and MVPA. Methods Using a multi-stage stratified and random cluster sampling method, 711 schools in Shanghai were selected (data were collected from October 2014 to February 2015). In total, 61,429 school-aged children (6–18 years old, 50.7% boys) and their parents were included. Self-reported questionnaires were used to measure sociodemographic characteristics, MVPA and various kinds of parental support, including parental encouragement (PAEN), parental involvement (PAIV), parental financial support (PAFS) and, parental modeling (PAMD). Descriptive statistics and Chi-square were used to report the level of MVPA and its difference across various kinds of parental support by gender groups. The logistic regression analysis was used to examine the associations between parental support and MVPA with odds ratios (ORs) and 95% confidence intervals (CIs). Results Overall, 19.4% of children and adolescents accumulated MVPA at least 60 min/day. Boys were more physically active than girls (21.4% > 17.4%, p Conclusions Less than one fifth of children and adolescents accumulated 60 min MVPA per day. Various kinds of parental support have important effects on children and adolescents’ MVPA, which varied by gender and grades. PAMD, in particular, should be emphasized more than PAEN, PAIV and PAFS in family-based interventions aiming at increasing PA in the future.

The durability of silty clay embankments is partially controlled by the moisture migration, which depends on soil hydraulic properties. This paper presents an experimental study of hydraulic properties of compacted binary silty clay. Specimens with different mixing ratios and dry densities were prepared. Scanning electron microscopy and mercury intrusion porosimetry were used to characterise the microstructure of silty clay. Thereafter, falling-head permeability tests and water retention tests were conducted to study the permeability and water retention property, respectively. The results demonstrate that clay particles are dispersed and show preferred arrangements after compaction when the clay content is 100%. As the clay content decreases, the arrangement of clay particles is gradually disturbed because of the existence of silt particles, causing the formation of large pores around silt particles. When the dry density increases, the pores around silt particles significantly decrease. Moreover, the permeability of silty clay decreases but the water retention capacity increases with increasing clay content and dry density. This is because the silty clay with larger clay content and dry density has fewer large pores, which greatly restrains the flow of water. Both the permeability and water retention property of silty clay can be predicted from pore size distribution parameters.

Background Rheumatoid arthritis (RA) is a common inflammatory disease with a substantial burden for society and economic worldwide. Chinese patent medicines (CPMs) have gained attention as alternative remedies due to they can exert the satisfactory therapeutic effects via holistic regulation. Currently, several oral Chinese patent medicines are routinely recommended for managing and treating RA. Therefore, a network meta-analysis (NMA), which tries to synthesize evidences for a decision making by evaluating the comparative effectiveness of multiple interventions against the same disease, was undertaken to identify the optimal intervention according to their efficacy in clinical treatment and symptom remission, safety profile and daily cost. Methods Randomized controlled trials (RCTs) regarding CPMs to treat RA were comprehensive retrieved from 3 foreign databases and 4 Chinese databases, and the retrieved results were last updated on January 10, 2019. The bias of the selected trials was assessed by two individuals independently through RoB2. A random-effects model was adopted during the meta-analytic procedures, and outcomes concerning efficacy and safety were evaluated as odds ratios (OR), mean differences (MD) and 95% credible intervals (CI) utilizing Stata 14.1 and WinBUGS 1.4.3 software. Furthermore, the cluster analysis and comprehensive investigation were preformed concerning the comparative efficacy, safety and cost of oral CPMs. Results One hundred sixteen RCTs involving 10,213 individuals met the inclusion criteria and were enrolled into current NMA. The results from existing evidence indicated that Biqi capsule and Yuxuebi capsule probably had a favorable balance in consideration of benefits, tolerability and daily cost. Furthermore, as the least expensive choice, glucosides of Tripterygium Wilfordii tablet was associated with displaying a trend of relieving joint tenderness, joint swelling, and morning stiffness for patients with RA. Conclusion Biqi capsule, Yuxuebi capsule and glucosides of Tripterygium Wilfordii tablet were recommended for treating RA based on the favorable benefits in both clinical efficacy and symptoms, and they, meanwhile, might be associated with the more tolerable and acceptable therapeutic alternative in terms of safety profile and daily cost. Nevertheless, the additional results from high-quality, multi-center and head-to-head trials would be pivotal for supporting our findings.

Based on 4 annual waves of data from a large sample of Chinese college students (N = 2,329, Mage = 18.40 years old, SD = .85; 63.10% females), this study examines the within-person and between-person effects in the association between problematic Internet use (PIU) and mental health issues. Results of analyses using the developmental equilibrium model (i.e., an autoregressive, cross-lagged panel model) demonstrate a reciprocal positive association between PIU and mental health issues consistently across waves. In contrast, results of analyses utilizing the random intercept, cross-lagged panel model (i.e., a model that can disaggregate within-person and between-person effects) indicate a unidirectional positive within-person effect from PIU to mental health issues (rather than the reverse) consistently over time, while controlling for the between-person effects that exist when comparing different individuals. Such findings highlight the importance of disaggregating within-person and between-person effects in understanding the nature of the temporal dynamics of the association between PIU and mental health. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Background Hepatoid carcinoma (HC) is an extremely rare neoplasm that is morphologically similar to hepatocellular carcinoma. HC has been described in various organs; however, HC of the pancreas is extremely rare. To our knowledge, only 38 cases have been reported. We present a case of HC of the pancreas in a 36-year-old male patient. Case summary A 36-year-old cachexic man with no significant past medical history was transferred to our hospital with a history of painless jaundice, elevated blood glucose and significant weight loss. Lab tests showed elevated serum transaminases, bilirubin and alpha-fetoprotein levels. Magnetic resonance imaging of the upper abdomen showed a diffusely enlarged pancreas, appearing "sausage-shaped". Magnetic resonance cholangiopancreatography showed upstream ductal dilation secondary to stricture of the main pancreatic duct and the common bile duct, which were not visible. Immunohistochemistry of biopsied tissue from a percutaneous pancreatic biopsy showed tumor cell positivity for HepPar1, polyclonal carcinoembryonic antigen and CK19, suggestive of HC of the pancreas. The characteristics of 39 patients with HC of the pancreas were reviewed. Conclusion HC of the pancreas is more prevalent in males, and patients have a median age of 57 years. It is most commonly asymptomatic or presents as abdominal back pain, and the pancreatic tail is the most common location. At the time of diagnosis, liver metastasis is often present.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. Multiple long non-coding RNAs (lncRNAs) are recently identified as crucial oncogenic factors or tumour suppressors. In this study, we explored the effects of LINC00174 on the progression of HCC. Expression levels of LINC00174 and microRNA-320 (miR-320) in HCC tissue samples were measured using quantitative real-time polymerase chain reaction (qRT-PCR). The association between pathological indices and LINC00174 was also analysed. Human HCC cell lines Hep3B and Huh7 were used as cell models. CCK-8 and bromodeoxyuridine (BrdU) assays were used to assess the effect of LINC00174 on HCC cell line proliferation. Flow cytometry was used to study the effect of LINC00174 on HCC apoptosis. Transwell assay was conducted to detect the effect of LINC00174 on migration and invasion. Furthermore, luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to confirm the binding relationship between miR-320 and LINC00174. Additionally, western blot was used to detect the regulatory function of LINC00174 on oncogene S100 calcium binding protein A10 (S100A10). We demonstrated that LINC00174 expression in HCC clinical samples was significantly increased and this was correlated with higher T stage. Its overexpression remarkably accelerated proliferation and metastasis of HCC cells while reduced apoptosis. Accordingly, knockdown of it suppressed the malignant phenotypes of HCC cells. Overexpression of LINC00174 significantly reduced the expression of miR-320 by sponging it, in turn enhanced the expression of S100A10. In conclusion, LINC00174 is a sponge of tumour suppressor miR-320, enhances the expression of S100A10 indirectly and functions as an oncogenic lncRNA in HCC. SIGNIFICANCE OF THE STUDY: LINC00174 is a novel lncRNA, whose function is rarely investigated. It is reported that it is oncogenic in colorectal cancer, while its role in HCC remains unclear. Herein, we report that LINC00174 is significantly up-regulated in HCC tissues and promotes the malignant phenotypes. We demonstrate that LINC00174 functions as a sponge for miR-320, increases the expression level of oncogene S100A10 in HCC. This study helps clarify the mechanism of HCC tumorigenesis and progression, and uncover the role of LINC00174 in human disease.

Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC)1-4. BCAA transaminase 2 (BCAT2) was essential for the collateral lethality conferred by deletion of malic enzymes in PDAC and the BCAA-BCAT metabolic pathway contributed to non-small-cell lung carcinomas (NSCLCs) other than PDAC3,4. However, the underlying mechanism remains undefined. Here we reveal that BCAT2 is elevated in mouse models and in human PDAC. Furthermore, pancreatic tissue-specific knockout of Bcat2 impedes progression of pancreatic intraepithelial neoplasia (PanIN) in LSL-KrasG12D/+; Pdx1-Cre (KC) mice. Functionally, BCAT2 enhances BCAA uptake to sustain BCAA catabolism and mitochondrial respiration. Notably, BCAA enhances growth of pancreatic ductal organoids from KC mice in a dose-dependent manner, whereas addition of branched-chain α-keto acid (BCKA) and nucleobases rescues growth of KC organoids that is suppressed by BCAT2 inhibitor. Moreover, KRAS stabilizes BCAT2, which is mediated by spleen tyrosine kinase (SYK) and E3 ligase tripartite-motif-containing protein 21 (TRIM21). In addition, BCAT2 inhibitor ameliorates PanIN formation in KC mice. Of note, a lower-BCAA diet also impedes PDAC development in mouse models of PDAC. Thus, BCAT2-mediated BCAA catabolism is critical for development of PDAC harbouring KRAS mutations. Targeting BCAT2 or lowering dietary BCAA may have translational significance.